DABT cheat sheet

Dose-response is the central principle: response severity and incidence generally increase with dose, and a substance may be harmless below a threshold and toxic above it.

LD50 is the median lethal dose; a lower LD50 denotes greater acute lethality, but LD50 alone does not capture chronic, organ-specific, or mechanism-based toxicity.

Therapeutic index = TD50 / ED50; a larger ratio indicates a wider separation between median toxic and median effective doses.

NOAEL is the highest dose with no statistically or biologically significant adverse effect versus control; LOAEL is the lowest dose with an observed adverse effect.

Potency is reflected by the dose at which a defined response occurs, such as ED50, not by the maximum response, which is efficacy.

Hormesis is a biphasic dose-response with low-dose stimulation or protection and high-dose inhibition or toxicity.

For non-genotoxic effects, a threshold is generally assumed because repair, detoxification, and clearance must be overwhelmed; for genotoxic carcinogens, default risk models often assume no threshold.

Receptor ligands can be full agonists, partial agonists, antagonists, or inverse agonists; effect depends on intrinsic activity and receptor reserve.

ADME, meaning absorption, distribution, metabolism, and excretion, determines the concentration-time profile at target sites.

Apparent volume of distribution Vd = amount in body / plasma concentration; large Vd indicates extensive tissue distribution or binding.

For first-order elimination, clearance CL = dose/AUC after intravenous dosing, and half-life t1/2 = 0.693 × Vd / CL.

AUC is estimated by trapezoidal integration of plasma concentration versus time; it reflects total systemic exposure.

Phase I reactions such as oxidation, reduction, and hydrolysis often introduce polar groups; cytochrome P450 oxidation is a major route and can bioactivate xenobiotics.

Phase II conjugation, including glucuronidation, sulfation, glutathione conjugation, and acetylation, generally increases water solubility and facilitates excretion.

First-pass hepatic and intestinal metabolism reduces oral bioavailability; saturable first-pass metabolism can cause disproportionate increases in systemic exposure with dose.

Michaelis-Menten kinetics: at low substrate, elimination is first-order; at high substrate, enzymes saturate and elimination becomes zero-order, or a constant amount per time.

Enterohepatic recirculation can prolong half-life when conjugates are hydrolyzed in the gut and reabsorbed.

Hepatic zonation: zone 3, or centrilobular, has high cytochrome P450 activity and lower glutathione, making it vulnerable to acetaminophen and carbon tetrachloride.

Zone 1, or periportal, has higher oxygen tension and glutathione; injury patterns help identify mechanism and culprit.

Proximal tubules are a principal renal target because they actively transport and concentrate filtered xenobiotics; heavy metals and aminoglycosides are examples.

Organophosphate and carbamate insecticides inhibit acetylcholinesterase, producing cholinergic excess: salivation, lacrimation, urination, diarrhea, bronchoconstriction, bradycardia, and fasciculations.

hERG potassium channel blockade delays cardiac repolarization, prolongs QT, and increases torsades de pointes risk.

Anthracyclines cause cumulative dose-related cardiomyopathy; bleomycin and paraquat are associated with pulmonary injury and fibrosis.

Benzene exposure is linked to bone marrow suppression and leukemia; chloramphenicol can cause dose-independent aplastic anemia.

Skin toxicity is classified as irritant contact dermatitis, from direct damage, or allergic contact dermatitis, a type IV cell-mediated sensitization.

Developmental toxicity depends on the exposure window; the embryonic period is often most sensitive to structural malformations.

Lead inhibits delta-aminolevulinic acid dehydratase and ferrochelatase, impairing heme synthesis and causing microcytic anemia and neurodevelopmental effects.

Cadmium accumulates in proximal renal tubules and causes tubular proteinuria; itai-itai disease includes osteomalacia and renal injury.

Methylmercury is neurotoxic, especially during fetal development; fish consumption is a major human exposure route.

Organophosphate poisoning: atropine for muscarinic effects and pralidoxime to reactivate acetylcholinesterase before aging; carbamates are reversible and generally do not require pralidoxime.

Cyanide blocks cytochrome c oxidase; hydroxocobalamin or sodium thiosulfate are antidotes. Methanol and ethylene glycol are treated with fomepizole or ethanol to block alcohol dehydrogenase.

Acetaminophen overdose depletes glutathione and allows NAPQI to bind hepatic proteins; N-acetylcysteine replenishes glutathione.

Warfarin inhibits vitamin K epoxide reductase; vitamin K reverses anticoagulation. Statins can cause myopathy, aminoglycosides nephrotoxicity and ototoxicity, and NSAIDs renal and gastrointestinal injury.

Natural toxins: tetrodotoxin blocks voltage-gated sodium channels; botulinum toxin inhibits acetylcholine release; aflatoxin B1 is a hepatocarcinogenic mycotoxin.

Biologicals can cause immunogenicity, cytokine release, and hypersensitivity; endotoxin, or lipopolysaccharide, triggers innate immune activation through TLR4.

Risk assessment has four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization.

Reference dose (RfD) = NOAEL or benchmark dose divided by uncertainty factors; default factors often include 10 for interspecies and 10 for intraspecies variability.

Margin of exposure (MOE) = point of departure / estimated exposure; a larger MOE indicates lower concern.

Cancer risk = dose × cancer slope factor; acceptable excess lifetime cancer risk is commonly set between 1×10^-6 and 1×10^-4.

Relative risk = incidence in exposed / incidence in unexposed; odds ratio approximates relative risk when the outcome is rare.

Attributable risk = incidence in exposed − incidence in unexposed; it estimates excess incidence associated with exposure.

Bradford Hill criteria include strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy; temporality is required.

Regulatory limits differ: OSHA PELs are enforceable, NIOSH RELs are recommended, ACGIH TLVs are guidelines, and EPA IRIS provides toxicity values for risk assessment.

ADI = NOAEL / safety factor; it estimates daily intake judged acceptable over a lifetime.

Randomization balances known and unknown confounders across groups; blinding reduces observer and reporting bias.

Cohort studies follow exposed and unexposed groups and estimate incidence and relative risk; case-control studies compare past exposures and estimate odds ratios.

Case-control designs are efficient for rare outcomes but vulnerable to recall and selection bias; cohort designs can establish temporality but are costly and prone to loss to follow-up.

Dose selection in repeat-dose studies uses range-finding and usually includes a low dose without expected toxicity, a mid dose, and a high dose with detectable toxicity but not excessive mortality.

Negative controls receive vehicle or no treatment; positive controls use a known toxicant to confirm assay sensitivity and performance.

Statistical significance, reflected by a p-value, does not equal biological relevance; effect size, dose-response, consistency, and power must be interpreted together.

Good Laboratory Practice requires written protocols, standard operating procedures, trained personnel, calibrated equipment, raw data retention, quality assurance, and audited reports.

Benchmark dose modeling fits a dose-response curve and derives a BMD and BMDL; the BMDL is often used as a point of departure instead of a NOAEL.

Species differences in metabolism, receptor affinity, and physiology limit direct animal-to-human extrapolation; uncertainty factors and physiologically based models address this.